The present invention, in some embodiments thereof, relates to methods and pharmaceutical compositions for improving wound healing in a subject by administering to the subject a therapeutically effective amount of CD24, and more particularly, but not exclusively, to methods of improving wound healing by topical administration of CD24.
Healthy individuals rarely have problems with wound healing. Most skin lesions heal rapidly and efficiently within one to two weeks (1). However, many medical and surgical complications can be attributed to deficiencies in wound repair. Thus, in many cases, although the wounds are healed, the outcome is neither esthetically nor functionally perfect (2). In the U.S. alone, 35 million cutaneous wounds require major intervention annually (2). Open wounds have lost the barrier that protects tissues from bacterial invasion and allows the escape of vital fluids. Without expeditious healing, infections become more frequent.
Normal wound healing is a complex, dynamic and fragile process that is impacted by many factors and is divided into three phases, inflammatory, proliferative and maturation or remodeling (3, 4). After an initial wound, a fibrin clot is formed. In the inflammatory phase, debris and bacteria undergo phagocytosis and removal. Cytokines are released to initiate the proliferative phase. This process manifests with chemotaxis, phagocytosis, angiogenesis, epithelization, collagen degradation and remodeling, production of new glycosaminoglycans and wound contraction. Wound healing is a highly regulated interplay between systematic expressed cell types (i.e., neutrophils, macrophages, fibroblasts, keratinocytes, and endothelial cells), extracellular matrix insoluble components and a group of soluble mediators (i.e., growth factors, cytokines, and chemokines) (2, 3, 5).
The healing process begins with an accumulation of neutrophils and monocytes in the damaged tissue to form a first line of defense. Thereafter, macrophages and mast cells emigrate from nearby tissues and the circulation and accumulate in order to initiate the specific immune response. These inflammatory cells are recruited to the wound site by specific chemotactic factors or chemokines (6, 7). Re-epithelialization and granulation tissue formation include migration of cells from the wound edge to fill the wound site. It involves the migration of keratinocytes over the impermanent matrix in order to rebuild a protective layer (8).
Rapid changes in the extracellular matrix (ECM) occur during the healing process. The fibrin clot is replaced by fibronectin and hyaluronan and subsequently by type I and III collagen (1). The contribution of each component to the wound repair process is difficult to assess due to the complexity of cells involved in the healing.
CD24 plays an important role in the adaptive immune response and controls an important genetic checkpoint for homeostasis and autoimmune diseases in both mice and humans. The CD24 gene encodes a heavily glycosylated cell surface protein anchored to the membrane by phosphatidylinositol (6). Human CD24 consists of 31 amino acids with 16 potential O-glycosylation and N-glycosylation sites. Owing to this extensive glycosylation, CD24 has mucin-like characteristics (9). It plays a crucial role in cell selection and maturation during hematopoiesis and is expressed mainly on premature lymphocytes and certain epithelial and neural cells (10, 11). CD24 can function as an alternative ligand for P-selectin, an adhesion receptor on activated endothelial cells and platelets (12-14).
CD24 has been previously shown to play an important role in the inflammation (15) process. Previous studies by the present inventors also showed that overexpression of CD24 increased proliferation, and migration rates in vitro (16-18).